This invention relates to the use of an irreversible inhibitor of GABA-transaminase for the treatment of substance addiction and modification of behavior associated with substance addiction. Substance addiction, such as drug abuse, and the resulting addiction-related behaviors are enormous social and economic problems that continue to grow with devastating consequences.
The addictive liability of drugs of abuse, such as for example, cocaine, nicotine, methamphetamine, morphine, heroin, ethanol, phencyclidine, methylenedioxmethamphetamine or other drugs of abuse has been linked to their pharmacological actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma-amino butyric acid (GABA).
Virtually all drugs of abuse, including nicotine, have been shown to acutely increase extracellular dopamine concentrations in the nucleus accumbens of mammals. This increase is clearly associated with the addictive liability of these compounds. Based on this unique biochemical fingerprint, drugs that attenuate or abolish this response may be quite effective for the treatment of substance abuse.
Substance addiction can occur by use of legal and illegal substances. Nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine (PCP), methylenedioxymethamphetamine (MDMA), and other addictive substances are readily available and routinely used by large segments of the United States population.
Many drugs of abuse are naturally occurring. For example, cocaine is a naturally occurring nonamphetamine stimulant derived from the leaves of the coca plant, Erythroylon coca. Coca leaves contain only about one-half of one percent pure cocaine alkaloid. When chewed, only relatively modest amounts of cocaine are liberated, and gastrointestinal absorption is slow. Certainly, this explains why the practice of chewing coca leaves has never been a public health problem in Latin America. The situation changes sharply with the abuse of the alkaloid itself.
It has been found that addicting drugs such as nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine and methylenedioxymethamphetamine enhance (in some cases directly, in other cases indirectly or even trans-synaptically) dopamine (DA) within the mesotelencephalic reward/reinforcement circuitry of the forebrain, presumably producing the enhanced brain reward that constitutes the drug user's “high.”
Alterations in the function of these DA systems have also been implicated in drug craving and in relapse to the drug-taking habit in recovering addicts. For example, cocaine acts on these DA systems by binding to the dopamine transporter (DAT) and preventing DA reuptake into the presynaptic terminal.
There is considerable evidence that nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine, methylenedioxymethamphetamine and other abused drugs' addictive liability is linked to a re-uptake blockade in the central nervous systems' (CNS') reward/reinforcement pathways. For example, cocaine-induced increases in extracellular DA have been linked to its rewarding and craving effects in rodents.
In humans, the pharmacokinetics binding profile of 11C-cocaine indicates that the uptake of labeled cocaine is directly correlated with the self-reported “high”. In addition, human cocaine addicts exposed to cocaine-associated environmental cues experienced increased cocaine craving which is antagonized by the DA receptor antagonist haloperidol. Based upon the presumptive link between cocaine's addictive liability and the DA reward/reinforcement circuitry of the forebrain, many pharmacologic strategies for treating cocaine addiction have been proposed.
In the past, one treatment strategy was to target directly the DAT with a high-affinity cocaine analog, thereby blocking cocaine's binding. Another treatment strategy was to modulate synaptic DA directly by the use of DA agonists or antagonists. Yet another treatment strategy was to modulate synaptic DA, indirectly or trans-synaptically, by specifically targeting a functionally-linked but biochemically different neurotransmitter system.
A number of drugs have been suggested for use in weaning cocaine users from their dependency. Certain therapeutic agents were favored by the “dopamine depletion hypothesis.” It is well established that cocaine blocks dopamine reuptake, acutely increasing synaptic dopamine concentrations. However, in the presence of cocaine, synaptic dopamine is metabolized as 3-methoxytyramine and excreted. The synaptic loss of dopamine places demands on the body for increased dopamine synthesis, as evidenced by the increase in tyrosine hydroxylase activity after cocaine administration. When the precursor supplies are exhausted, a dopamine deficiency develops.
The above hypothesis led to the testing of bromocriptine, a dopamine receptor agonist. Another approach was the administration of amantadine, a dopamine releaser. Yet another approach, also based on the dopamine depletion hypothesis, was to provide a precursor for dopamine, such as L-dopa.
Agonists are not preferred therapeutic agents. A given agonist may act on several receptors, or similar receptors on different cells, not just on the particular receptor or cell one desires to stimulate. As tolerance to a drug develops (through changes in the number of receptors and their affinity for the drug), tolerance to the agonist may likewise develop. A particular problem with the agonist bromocriptine, for example, is that it may itself create a drug dependency. Thus, treatment strategies used in the past did not relieve the patient's craving for cocaine. Moreover, by using certain agonists such as bromocriptine, a patient was likely to replace one craving for another.
Another drug that is frequently abused is nicotine. The alkaloid (−)-nicotine is present in cigarettes and other tobacco products that are smoked or chewed. It has been found that nicotine contributes to various diseases, including cancer, heart disease, respiratory disease and other conditions, for which tobacco use is a risk factor, particularly heart disease.
Vigorous campaigns against the use of tobacco or nicotine have taken place, and it is now common knowledge that the cessation of tobacco use brings with it numerous unpleasant withdrawal symptoms, which include irritability, anxiety, restlessness, lack of concentration, lightheadedness, insomnia, tremor, increased hunger and weight gain, and, of course, an intense craving for tobacco.
The addictive liability of nicotine has been linked to the rewarding/reinforcing actions and its effects on DA neurons in the reward pathways of the brain (Nisell et al., 1995; Pontieri, et al., 1996). For example, the acute systemic administration of nicotine, as well as numerous other drugs of abuse, produces an increase in extracellular DA levels in the nucleus accumbens (NACC), an important component of the reward system (Damsma et al., 1989; Di Chiara and Imperato, 1988; Imperato et al., 1986; Nisell et al., 1994a, 1995; Pontieri et al., 1996). Similarly, the infusion of nicotine into the ventral segmental area (VTA) of the rodent produces a significant increase in DA levels in the NACC (Nisell et al., 1994b).
A few pharmaceutical agents have been reported as useful to treat nicotine dependence, including nicotine substitution therapy such as nicotine gum, transdermal nicotine patches, nasal sprays, nicotine inhalers and bupropion, the first nonnicotinic treatment for smoking cessation (Henningfield, 1995; Hurt, et al., 1997).
Unfortunately, nicotine substitution therapy involves the administration of the nicotine which frequently leads to nicotine withdrawal and subsequent relapse to use of tobacco products. Thus, there is a need for a therapy having a desirable side effect profile, to relieve nicotine withdrawal symptoms, including the long term cravings for nicotine.
Other known addictive substances are narcotic analgesics such as morphine, heroin and other opioids both natural and semisynthetic. Abuse of opioids induce tolerance and dependence. Withdrawal symptoms from the cessation of opioids use vary greatly in intensity depending on numerous factors including the dose of the opioid used, the degree to which the opioid effects on the CNS are continuously exerted, the duration of chronic use, and the rate at which the opioid is removed from the receptors.
These withdrawal symptoms include craving, anxiety, dysphoria, yawning, perspiration, lacrimation, rhinorrhoea, restless and broken sleep, irritability, dilated pupils, aching of bones, back and muscles, piloerection, hot and cold flashes, nausea, vomiting, diarrhea, weight loss, fever, increased blood pressure, pulse and respiratory rate, twitching of muscles and kicking movements of the lower extremities.
Medical complications associated with injection of opioids include a variety of pathological changes in the CNS including degenerative changes in globus pallidus, necrosis of spinal gray matter, transverse myelitis, amblyopia, plexitis, peripheral neuropathy, Parkinsonian syndromes, intellectual impairment, personality changes, and pathological changes in muscles and peripheral nerves. Infections of skin and systemic organs are also quite common including staphylococcal pneumonitis, tuberculosis, endocarditis, septicemia, viral hepatitis, human immunodeficiency virus (HIV), malaria, tetanus and osteomyelitis. The life expectancy of opioid addicts is markedly reduced, due to overdose, drug-related infections, suicide and homicide.
Pharmaceutical agents used in treating opioid dependence include methadone, which is an opioid, and opioid antagonists, primarily naloxone and naltrexone. Clonidine has been shown to suppress some elements of opioid withdrawal but suffers from the side effects of hypotension and sedation, which can be quite extreme. Behavior-modifying psychological treatment and training are frequently adjunctive therapy used in association with pharmaceutical agents. There is a need for a therapy having a more desirable side effect profile, to relieve opioid addiction and withdrawal symptoms.
Ethanol is probably the most frequently used and abused depressant in most cultures and a major cause of morbidity and mortality. Repeated intake of large amounts of ethanol can affect nearly every organ system in the body, particularly the gastrointestinal tract, cardiovascular system, and the central and peripheral nervous systems. Gastrointestinal effects include gastritis, stomach ulcers, duodenal ulcers, liver cirrhosis, and pancreatitis.
Further, there is an increased rate of cancer of the esophagus, stomach and other parts of the gastrointestinal tract with ethanol abuse. Cardiovascular effects include hypertension, cardiomyopathy and other myopathies, significantly elevated levels of triglycerides and low-density lipoprotein cholesterol. These cardiovascular effects contribute to a marked increase risk of heart disease.
Ethanol abuse can manifest in peripheral neuropathy as evidenced by muscular weakness, parathesias, and decreased peripheral sensation. Central nervous system effects include cognitive deficits, severe memory impairment degenerative changes in the cerebellum, and ethanol-induced persisting amnesiac disorder in which the ability to encode new memory is severely impaired. Generally, these effects are related to vitamin deficiencies, particularly the B vitamins.
Individuals with ethanol dependence or addiction exhibit symptoms and physical changes including dyspepsia, nausea, bloating, esophageal varices, hemorrhoids, tremor, unsteady gait, insomnia, erectile dysfunction, decreased testicular size, feminizing effects associated with reduced testosterone levels, spontaneous abortion, and fetal alcohol syndrome. Symptoms associated with ethanol cessation or withdrawal include nausea, vomiting, gastritis, hematemises, dry mouth, puffy blotchy complexion, and peripheral edema.
The generally accepted treatment of ethanol addiction and withdrawal is accomplished by administering a mild tranquilizer such a chlordiazepoxide. Typically, vitamins, particularly the B vitamins, are also administered. Optionally, magnesium sulfate and/or glucose are also administered. Nausea, vomiting and diarrhea are treated symptomatically at the discretion of the attending physician. Disulfiram may also be administered for help in maintaining abstinence. If ethanol is consumed while on disulfiram, acetaldehyde accumulates producing nausea and hypotension. There is a need for a therapy having a more desirable side effect profile, to relieve ethanol addiction and withdrawal symptoms.
Recently, it has been reported that polydrug or combination drug abuse has been increasing at an alarming rate. For example, cocaine and heroin are often abused together in a drug combination known as a “speedballing.” Such reported increase is believed to be a result of a synergistic effect that increases the euphoria of the user.
In many instances, drug dealers combine various drugs of abuse to increase the intensity of the “high.” This is especially prevalent where the drug user is a regular customer and has built up a tolerance to the drug alone. Most times the drug user is unaware of this dangerous combining.
Phencyclidine, commonly known as PCP, is described as dissociative in action. This means that the mind feels separated from the body. PCP was first used as an anesthetic for surgery in the 1950's. Due to the highly undesirable side effects, such as convulsions and hallucinations, its use was discontinued.
The first reports of the illicit use of PCP originated in late 1960's. However, due to numerous reports of bad experiences, PCP lost popularity. In the 1970's PCP use re-emerged by itself and in combination with other illicit drugs such as marijuana and cocaine. PCP continues to be an abused substance. Many people after using it once, will not choose to use it again. Others use it consistently and regularly. A numbing effect on pain, both emotional and physical is one reason why others say they use PCP.
PCP is a synthetic substance that can be in the form of a pill, powder or liquid suspension. It can be smoked, snorted, orally ingested or intravenously administered. The short-term effects can last for hours or days and include rapid breathing, increased blood pressure and heart rate, increased temperature, profuse sweating, bizarre postures and muscle jerking. Higher doses can cause vomiting, blurred vision, convulsions and coma.
The long-term effects of PCP include flashbacks, speech problems, loss of memory, anxiety, depression and social withdrawal. Frequent users report the need to increase intake to maintain a ‘high’. There is no known accepted treatment for PCP abuse.
Methylenedioxymethamphetamine (MDMA), commonly known as “ecstacy,” is a synthetic psychoactive drug possessing stimulant and hallucinogenic properties. MDMA was first synthesized in 1912 as a possible appetite suppressant. Illicit use of MDMA did not become popular until the late 1980's.
MDMA is usually taken orally and its effects can last from four to six hours. Users say that it produces profoundly positive feelings and extreme relaxation. MDMA is also said to suppress the need to eat, drink or sleep. Consequently, MDMA use sometimes results in severe dehydration or exhaustion.
MDMA users may encounter problems similar to those of amphetamine and cocaine users, which includes addiction. In addition, MDMA can cause confusion, depression, sleep problems, anxiety, and paranoia. Physical effects of MDMA use include muscle tension, involuntary teeth clenching, nausea, blurred vision, faintness and chills or sweating.
The effects of long term MDMA use are just beginning to undergo scientific analysis. The National Institute of Mental Health conducted a study of habitual MDMA users in 1998 that revealed damage to the neurons of the brain that transmit serotonin. Serotonin is an important biochemical involved in a variety of critical functions including learning, sleep and integration of emotion. The results of the study indicate that MDMA users are at risk of developing permanent brain damage that may manifest itself in depression, anxiety, memory loss and other neuropsychotic disorders. There is no known and accepted treatment for MDMA abuse.
Accordingly, there is a need in the treatment of addiction to drugs of abuse to provide new methods which can relieve a patient's craving by changing the pharmacological actions of drugs of abuse in the central nervous system. There is also a need to provide new methods to treat combination drug abuse.